Indications and Usage for Dymista

Seasonal Allergic Rhinitis

Dymista nasal spray is indicated for the relief of symptoms of seasonal allergic rhinitis in patients 6 years of age and older who require treatment with both azelastine hydrochloride and fluticasone propionate for symptomatic relief.

Dymista Dosage and Administration

Dosing Information

The recommended dosage of Dymista is 1 spray in each nostril twice daily.

Dosage Forms and Strengths

Contraindications

None.

Warnings and Precautions

Somnolence

In clinical trials, the occurrence of somnolence has been reported in some patients (6 of 853 adult and adolescent patients and 2 of 416 children) taking Dymista in placebo controlled trials [see Adverse Reactions (6.1)]. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as operating machinery or driving a motor vehicle after administration of Dymista. Concurrent use of Dymista with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur [see Drug Interactions (7.1)].

Local Nasal Effects

In clinical trials of 2 to 52 weeks' duration, epistaxis was observed more frequently in patients treated with Dymista than those who received placebo [see Adverse Reactions (6)].

Instances of nasal ulceration and nasal septal perforation have been reported in patients following the intranasal application of corticosteroids. There were no instances of nasal ulceration or nasal septal perforation observed in clinical trials with Dymista.

Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should avoid use of Dymista until healing has occurred.

In clinical trials with fluticasone propionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with Dymista. Patients using Dymista over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa.

Glaucoma and Cataracts

Nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

Glaucoma and cataract formation were evaluated with intraocular pressure measurements and slit lamp examinations in a controlled 12-month study in 612 adolescent and adult patients aged 12 years and older with perennial allergic or vasomotor rhinitis (VMR). Of the 612 patients enrolled in the study, 405 were randomized to receive Dymista (1 spray per nostril twice daily) and 207 were randomized to receive fluticasone propionate nasal spray (2 sprays per nostril once daily). In the Dymista group, one patient had increased intraocular pressure at month 6. In addition, three patients had evidence of posterior subcapsular cataract at month 6 and one at month 12 (end of treatment). In the fluticasone propionate group, three patients had evidence of posterior subcapsular cataract at month 12 (end of treatment).

Immunosuppression

Persons who are using drugs, such as corticosteroids, that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract; untreated local or systemic fungal or bacterial infections; systemic viral or parasitic infections; or ocular herpes simplex because of the potential for worsening of these infections.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Effects

When intranasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of Dymista should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. The concomitant use of intranasal corticosteroids with other inhaled corticosteroids could increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis.

The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms.

Use caution with the coadministration of Dymista and other potent CYP3A4 inhibitors, such as ketoconazole [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Effect on Growth

Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving Dymista [see Use in Specific Populations (8.4)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.

Adults and Adolescents 12 Years of Age and Older

The safety data described below in adults and adolescents 12 years of age and older reflect exposure to Dymista in 853 patients (12 years of age and older; 36% male and 64% female) with seasonal allergic rhinitis in 3 double-blind, placebo-controlled clinical trials of 2-week duration. The racial distribution for the 3 clinical trials was 80% white, 16% black, 2% Asian, and 1% other.

In the 3 placebo controlled clinical trials of 2-week duration, 3411 patients with seasonal allergic rhinitis were treated with 1 spray per nostril of Dymista, azelastine hydrochloride nasal spray, fluticasone propionate nasal spray, or placebo, twice daily. The azelastine hydrochloride and fluticasone propionate comparators use the same vehicle and device as Dymista and are not commercially marketed. Overall, adverse reactions were 16% in the Dymista treatment groups, 15% in the azelastine hydrochloride nasal spray groups, 13% in the fluticasone propionate nasal spray groups, and 12% in the placebo groups. Overall, 1% of patients in both the Dymista and placebo groups discontinued due to adverse reactions.

Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with Dymista in the seasonal allergic rhinitis controlled clinical trials.

Table 1. Adverse Reactions with ≥2% Incidence and More Frequently than Placebo in Placebo-Controlled Trials of 2 Weeks Duration with Dymista in Adult and Adolescent Patients With Seasonal Allergic Rhinitis

*Safety population N=853, intent-to-treat population N=848† Not commercially marketed

1 spray per nostril twice daily

Dymista
(N=853)*

Azelastine
Hydrochloride Nasal
Spray†
(N=851)

Fluticasone Propionate
Nasal Spray†
(N=846)

Vehicle Placebo
(N=861)

Dysgeusia

30(4%)

44(5%)

4(1%)

2(<1%)

Headache

18(2%)

20(2%)

20(2%)

10(1%)

Epistaxis

16(2%)

14(2%)

14(2%)

15(2%)

In the above trials, somnolence was reported in <1% of patients treated with Dymista (6 of 853) or vehicle placebo (1 of 861) [see Warnings and Precautions (5.1)].

Pediatric Patients 6-11 Years of Age

The safety data described below in children 6-11 years of age reflect exposure to Dymista in 152 patients (6-11 years of age; 57% male and 43% female) with seasonal allergic rhinitis in one double-blind, placebo-controlled clinical trial of 2-week duration. The racial distribution for the clinical trial was 69% white, 31% black, 2% Asian and 2% other.

In the placebo-controlled clinical trial of 2-week duration, patients with seasonal allergic rhinitis were treated with 1 spray per nostril of Dymista or placebo, twice daily. Overall, adverse reactions were 16% in the Dymista treatment group, and 12% in the placebo group. Overall, 1% of patients in both the Dymista and placebo groups discontinued due to adverse reactions.

Table 2 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with Dymista in the seasonal allergic rhinitis controlled clinical trial.

Table 2. Adverse Reactions with ≥2% Incidence and More Frequently than Placebo in Placebo-Controlled Trials of 2 Weeks Duration with Dymista in Children 6 to 11 Years of Age With Seasonal Allergic Rhinitis

*Safety population N=152, intent-to-treat population N=152

1 spray per nostril twice daily

Dymista

(N=152)*

Vehicle Placebo

(N=152)

Dysgeusia

6 (4%)

0 (0%)

Epistaxis

6 (4%)

4 (3%)

In the above trial, somnolence was not reported [see Warnings and Precautions (5.1)].

Long-Term (12-Month) Safety Trial in Adults and Adolescents 12 Years of Age and Older:

In the 3-month, open label, active-controlled, safety trial in pediatric patients 6-11 years of age 264 patients (128 patients ≥6 to <9 years of age, and 136 patients ≥9 to <12 years of age) with allergic rhinitis (based on the Investigator’s assessment) were treated with Dymista, 1 spray per nostril twice daily and 89 patients (44 patients ≥6 to <9 years of age, and 45 patients ≥9 to <12 years of age) were treated with fluticasone propionate nasal spray, 1 spray per nostril twice daily. Overall, adverse reactions were 40% in the Dymista treatment group and 36% in the fluticasone propionate nasal spray group. The most frequently reported adverse reactions (≥2%) with Dymista were epistaxis, headache, oropharyngeal pain, vomiting, upper abdominal pain, cough, pyrexia, otitis media, upper respiratory tract infection, diarrhea, nausea, otitis externa, and urticaria. In the Dymista treatment group 23 patients (9%) had mild epistaxis and 3 patients (1%) had moderate epistaxis. In the fluticasone propionate nasal spray treatment group 8 patients (9%) had mild epistaxis. No patients had reports of severe epistaxis. Focused nasal examinations were performed and no ulcerations or septal perforations were observed. Four of 264 patients (2%) treated with Dymista and 3 of 89 (3%) treated with fluticasone propionate nasal spray discontinued from the trial due to adverse events. There were two reports of somnolence, one severe, among children taking Dymista [see Warnings and Precautions (5.1)].

Postmarketing Experience

The following spontaneous adverse events have been reported with Dymista or one of the components (azelastine and fluticasone). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Drug Interactions

No formal drug interaction studies have been performed with Dymista. The drug interactions of the combination are expected to reflect those of the individual components.

Central Nervous System Depressants

Concurrent use of Dymista with alcohol or other central nervous system depressants should be avoided because somnolence and impairment of central nervous system performance may occur [see Warnings and Precautions (5.1)].

Ketoconazole (also a strong CYP3A4 inhibitor), administered in multiple 200 mg doses to steady-state, increased plasma exposure of fluticasone propionate, reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol, following administration of a single 1000 mcg dose of fluticasone propionate by oral inhalation route.

Caution should be exercised when Dymista is coadministered with ketoconazole and other known strong CYP3A4 inhibitors.

USE IN SPECIFIC POPULATIONS

Pregnancy

Dymista: Teratogenic Effects: Pregnancy Category C:

There are no adequate and well-controlled clinical trials of Dymista, azelastine hydrochloride only, or fluticasone propionate only in pregnant women. Animal reproductive studies of azelastine hydrochloride and fluticasone propionate in mice, rats, and/or rabbits revealed evidence of teratogenicity as well as other developmental toxic effects. Because animal reproduction studies are not always predictive of human response, Dymista should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Azelastine hydrochloride: Teratogenic Effects: In mice, azelastine hydrochloride caused embryo-fetal death, malformations (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased fetal weight at an oral dose approximately 610 times the maximum recommended human daily intranasal dose (MRHDID) in adults (on a mg/m2 basis at a maternal dose of 68.6 mg/kg). This dose also caused maternal toxicity as evidenced by decreased body weight. Neither fetal nor maternal effects occurred at a dose that was approximately 26 times the MRHDID (on a mg/m2 basis at a maternal dose of 3 mg/kg).

In rats, azelastine hydrochloride caused malformations (oligo- and brachydactylia), delayed ossification and skeletal variations, in the absence of maternal toxicity, at an oral dose approximately 530 times the MRHDID in adults (on a mg/m2 basis at a maternal dose of 30 mg/kg). At a dose approximately 1200 times the MRHDID (on a mg/m2 basis at a maternal dose of 68.6 mg/kg), azelastine hydrochloride also caused embryo-fetal death and decreased fetal weight; however, this dose caused severe maternal toxicity. Neither fetal nor maternal effects occurred at a dose approximately 53 times the MRHDID (on a mg/m2 basis at a maternal dose of 3 mg/kg).

In rabbits, azelastine hydrochloride caused abortion, delayed ossification, and decreased fetal weight at oral doses approximately 1100 times the MRHDID in adults (on a mg/m2 basis at a maternal dose of 30 mg/kg); however, these doses also resulted in severe maternal toxicity. Neither fetal nor maternal effects occurred at a dose approximately 11 times the MRHDID (on a mg/m2 basis at a maternal dose of 0.3 mg/kg).

Fluticasone propionate:Teratogenic Effects: Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Subcutaneous studies in the mouse and rat at doses approximately equivalent to and 4 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal doses of 45 and 100 mcg/kg, respectively), revealed fetal toxicity characteristic of potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.

In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose less than the MRHDID in adults (on a mcg/m2 basis at a maternal dose of 4 mcg/kg). However, no teratogenic effects were reported at oral doses up to approximately 25 times the MRHDID in adults (on a mcg/m2 basis at a maternal dose of 300 mcg/kg) of fluticasone propionate to the rabbit. No fluticasone propionate was detected in the plasma in this study, consistent with the established low bioavailability following oral administration [see Clinical Pharmacology (12.3)].

Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.

Nonteratogenic Effects: Fluticasone propionate crossed the placenta following oral administration of approximately 4 and 25 times the MRHDID in adults (on a mcg/m2 basis at maternal doses of 100 mcg/kg and 300 mcg/kg to rats and rabbits, respectively).

Nursing Mothers

Dymista: It is not known whether Dymista is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when Dymista is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of Dymista by nursing mothers, based on data from the individual components, a decision should be made whether to discontinue nursing or to discontinue Dymista, taking into account the importance of Dymista to the mother.

Azelastine hydrochloride: It is not known if azelastine hydrochloride is excreted in human milk.

Fluticasone propionate: It is not known if fluticasone propionate is excreted in human milk. However, other corticosteroids are excreted in human milk. Subcutaneous administration to lactating rats of 10 mcg/kg of tritiated fluticasone propionate (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 basis) resulted in measurable radioactivity in the milk.

Pediatric Use

Use of Dymista for seasonal allergic rhinitis in pediatric patients 6 to 11 years of age is supported by safety and efficacy data from clinical studies (416 patients 6 to 11 years of age with allergic rhinitis were treated with Dymista in controlled clinical trials) and the established efficacy and safety of azelastine hydrochloride nasal spray and fluticasone propionate nasal spray in this age group [see Adverse Reactions(6.1) and Clinical Studies (14)].

Sixty-one patients ages 4-5 years of age were treated with Dymista in the pediatric studies described above. Safety findings in children 4-5 years of age were similar to those in children 6-11 years of age, but efficacy was not established.

Safety and effectiveness of Dymista has not been studied in pediatric patients below the age of 4 years.

Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including Dymista, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives.

Geriatric Use

Clinical trials of Dymista did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Overdosage

Dymista: Dymista contains both azelastine hydrochloride and fluticasone propionate; therefore, the risks associated with overdosage for the individual components described below apply to Dymista.

Azelastine hydrochloride: There have been no reported overdosages with azelastine hydrochloride. Acute azelastine hydrochloride overdosage by adults with this dosage form is unlikely to result in clinically significant adverse events, other than increased somnolence, since one (1) 23 g bottle of Dymista contains approximately 23 mg of azelastine hydrochloride. Clinical trials in adults with single doses of the oral formulation of azelastine hydrochloride (up to 16 mg) have not resulted in increased incidence of serious adverse events. General supportive measures should be employed if overdosage occurs. There is no known antidote to Dymista. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, Dymista should be kept out of the reach of children.

Fluticasone propionate: Chronic fluticasone propionate overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)]. Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated. Single oral fluticasone propionate doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg daily for 14 days in patients were well tolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo treatment groups. Acute overdosage with this dosage form is unlikely since one (1) 23 g bottle of Dymista contains approximately 8.5 mg of fluticasone propionate.

Dymista Description

Dymista (azelastine hydrochloride and fluticasone propionate) nasal spray is formulated as a white, uniform metered-spray suspension for intranasal administration. It is a fixed dose combination product containing an antihistamine (H1 receptor antagonist) and a corticosteroid as active ingredients.

Azelastine hydrochloride active ingredient occurs as a white, odorless, crystalline powder with a bitter taste. It has a molecular weight of 418.37. It is sparingly soluble in water, methanol, and propylene glycol and slightly soluble in ethanol, octanol, and glycerin. It has a melting point of 225°C and the pH of 5.2. Its chemical name is (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride. Its molecular formula is C22H24ClN3O•HCl with the following chemical structure:

Fluticasone propionate active ingredient is a white powder with a melting point of 273°C, a molecular weight of 500.6, and the empirical formula is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. Fluticasone propionate is a synthetic corticosteroid having the chemical name S-(fluoromethyl)-6α,9-difluoro-11β,-17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate, and the following chemical structure:

Dymista - Clinical Pharmacology

Mechanism of Action

Dymista: Dymista contains both azelastine hydrochloride and fluticasone propionate; therefore, the mechanisms of actions described below for the individual components apply to Dymista. These drugs represent two different classes of medications (histamine H1-receptor antagonist and synthetic corticosteroid).

Azelastine hydrochloride: Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine hydrochloride in Dymista is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in vitro studies. The major metabolite, desmethylazelastine, also possesses H1-receptor antagonist activity.

Fluticasone propionate: Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid receptor system involving binding and gene expression afforded 50% responses at 1.25 and 0.17 nM concentrations, respectively. Fluticasone propionate was 3-fold to 5-fold more potent than dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also support its potent glucocorticoid activity. The clinical relevance of these findings is unknown.

The precise mechanism through which fluticasone propionate affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation.

Pharmacodynamics

Cardiac Effects:

In a placebo-controlled trial (95 patients with allergic rhinitis), there was no evidence of an effect of azelastine hydrochloride nasal spray (2 sprays per nostril twice daily for 56 days) on cardiac repolarization as represented by the corrected QT interval (QTc) of the electrocardiogram. Following multiple dose oral administration of azelastine 4 mg or 8 mg twice daily, the mean change in QTc was 7.2 msec and 3.6 msec, respectively.

Interaction studies investigating the cardiac repolarization effects of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. These drugs had no effect on QTc based on analysis of serial electrocardiograms.

Pharmacokinetics

Absorption:

After intranasal administration of two sprays per nostril (548 mcg of azelastine hydrochloride and 200 mcg of fluticasone) of Dymista, the mean (± standard deviation) peak plasma exposure (Cmax) was 194.5 ± 74.4 pg/mL for azelastine and 10.3±3.9 pg/mL for fluticasone propionate and the mean total exposure (AUC) was 4217 ± 2618 pg/mL*hr for azelastine and 97.7 ± 43.1 pg/mL*hr for fluticasone. The median time to peak exposure (tmax) from a single dose was 0.5 hours for azelastine and 1.0 hours for fluticasone.

Systemic bioavailability of azelastine from Dymista following intranasal administration was comparable with monotherapy azelastine hydrochloride (Astelin®) nasal spray (i.e., approximately 40%). Systemic bioavailability of fluticasone from Dymista following intranasal administration was 44-61% higher than monotherapy fluticasone propionate (bioavailability for monotherapy fluticasone nasal spray was less than 2%). Due to the low intranasal bioavailability, pharmacokinetic data for fluticasone propionate were obtained via other routes of administration. Studies using oral dosing of radiolabeled fluticasone propionate showed negligible oral bioavailability and high extraction from plasma. The majority of the circulating radioactivity was due to an inactive metabolite.

Distribution:

Based on intravenous and oral administration, the steady-state volume of distribution of azelastine hydrochloride is 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein binding of azelastine hydrochloride and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively.

Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.

The percentage of fluticasone propionate bound to human plasma proteins averaged 91% with no obvious concentration relationship. Fluticasone propionate is weakly and reversibly bound to erythrocytes and freely equilibrates between erythrocytes and plasma. Fluticasone propionate is not significantly bound to human transcortin.

Metabolism:

Azelastine hydrochloride is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. The total clearance of azelastine is approximately 0.50 L/kg/hr.

For fluticasone propionate, the only circulating metabolite detected in man is the 17β-carboxylic acid derivative, which is formed through the CYP3A4 pathway. This inactive metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. The average total clearance of fluticasone propionate is relatively high (approximately 66 L/hr).

Elimination: Following intranasal administration of Dymista, the elimination half-life of azelastine hydrochloride is approximately 25 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.

Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.

Special Populations:

Dymista was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained.

Hepatic Impairment: Following oral administration of azelastine hydrochloride, pharmacokinetic parameters were not influenced by hepatic impairment.

Caution should be exercised when other strong CYP3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol. [see Drug Interactions (7.2)]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Dymista: No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with Dymista; however, studies are available for the individual active components, azelastine hydrochloride and fluticasone propionate, as described below.

Azelastine hydrochloride: In 2-year carcinogenicity studies in rats and mice, azelastine hydrochloride did not show evidence of carcinogenicity at oral doses up to 30 mg/kg and 25 mg/kg, respectively. These doses were approximately 530 and 220 times the maximum recommended human daily intranasal dose [MRHDID] on a mg/m2 basis.

Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses up to 30 mg/kg (approximately 530 times the MRHDID in adults on a mg/m2 basis). At 68.6 mg/kg (approximately 1200 times the MRHDID on a mg/m2 basis), the duration of estrous cycles was prolonged and copulatory activity and the number of pregnancies were decreased. The numbers of corpora lutea and implantations were decreased; however, pre-implantation loss was not increased.

Fluticasone propionate: Fluticasone propionate demonstrated no tumorigenic potential in mice at oral doses up to 1,000 mcg/kg (approximately 20 times the maximum recommended daily intranasal dose in adults and approximately 10 times the maximum recommended daily intranasal dose in children on a mcg/m2 basis) for 78 weeks or in rats at inhalation doses up to 57 mcg/kg (approximately 2 times the MRHDID in adults on a mcg/m2 basis) for 104 weeks.

Fluticasone propionate did not induce gene mutation in prokaryotic or eukaryotic cells in vitro. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro or in the mouse micronucleus test.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at subcutaneous doses up to 50 mcg/kg (approximately 2 times the MRHDID in adults on a mcg/m2 basis). Prostate weight was significantly reduced at a subcutaneous dose of 50 mcg/kg.

Clinical Studies

Adults and Adolescents 12 Years of Age and Older

The efficacy and safety of Dymista in adults and adolescents 12 years of age and older with seasonal allergic rhinitis was evaluated in 3 randomized, multicenter, double-blind, placebo-controlled clinical trials in 853 patients. The population of the trials was 12 to 78 years of age (64% female, 36% male; 80% white, 16% black, 2% Asian, 1% other).

Patients were randomized to one of four treatment groups: one spray per nostril twice daily of Dymista, azelastine hydrochloride nasal spray, fluticasone propionate nasal spray, and vehicle placebo. The azelastine hydrochloride and fluticasone propionate comparators use the same device and vehicle as Dymista and are not commercially marketed. Assessment of efficacy was based on the reflective total nasal symptom score (rTNSS), in addition to the instantaneous total nasal symptom score (iTNSS) and other supportive secondary efficacy variables. TNSS is calculated as the sum of the patients' scoring of the 4 individual nasal symptoms (rhinorrhea, nasal congestion, sneezing, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). Patients were required to record symptom severity daily reflecting over the previous 12 hours (morning, AM, and evening, PM). For the primary efficacy endpoint, the combined AM+PM rTNSS (maximum score of 24) was assessed as a change from baseline for each day and then averaged over a 2-week treatment period. The primary efficacy endpoint was the mean change from baseline in combined AM+PM rTNSS over 2 weeks. The iTNSS was recorded immediately prior to the next dose.

In these trials, Dymista demonstrated statistically significant greater decreases in rTNSS as compared to azelastine hydrochloride and to fluticasone propionate, as well as to placebo. The differences between the monotherapies and placebo also were statistically significant. Representative results from one of the trials are shown below (Table 3).

Table 3. Mean Change from Baseline in Reflective Total Nasal Symptom Scores over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis

* Sum of AM and PM rTNSS for each day (Maximum Score =24) and averaged over the 14 day treatment period† Not commercially marketed

LS Mean, 95% CI, and p-value are obtained from the repeated-measures analysis of covariance model using observed data.

Baseline

Change from
Baseline

Difference From Dymista Nasal Spray

Treatment
(one spray /nostril twice daily)

N

LS Mean

LS Mean

LS Mean

95% CI

P-value

Dymista

207

18.3

-5.6

--

--

--

Azelastine HCl Nasal Spray†

208

18.3

-4.3

-1.4

(-2.2, -0.5)

0.002

Fluticasone Propionate Nasal Spray†

207

18.2

-4.7

-1.0

(-1.8, -0.2)

0.022

Placebo

209

18.6

-2.9

-2.7

(-3.5, -1.9)

<0.001

In these trials, Dymista also demonstrated statistically significant, greater decreases in iTNSS as compared to placebo, as did the azelastine hydrochloride and fluticasone propionate comparators. Representative results from one of the trials are shown below (Table 4).

Table 4. Mean Change from Baseline in Instantaneous Total Nasal Symptom Scores over 2 Weeks* in Adults and Children ≥ 12 years with Seasonal Allergic Rhinitis

* Sum of AM and PM iTNSS for each day (Maximum Score =24) and averaged over the 14 day treatment period† Not commercially marketed

LS Mean, 95% CI, and p-value are obtained from the repeated-measures analysis of covariance model using observed data.

Baseline

Change from
Baseline

Difference From Placebo

Treatment
(one spray /nostril twice daily)

N

LS Mean

LS Mean

LS Mean

95% CI

P-value

Dymista

207

17.2

-5.2

-2.6

(-3.4, -1.8)

<0.001

Azelastine HCl Nasal Spray†

208

16.8

-3.9

-1.3

(-2.0, -0.6)

<0.001

Fluticasone Propionate Nasal Spray†

207

16.8

-4.5

-1.9

(-2.6, -1.2)

<0.001

Placebo

209

17.3

-2.7

--

--

--

Onset of action, defined as the first timepoint at which Dymista was statistically superior to placebo in the mean change from baseline in iTNSS and which was sustained thereafter, was assessed in each of the three trials. Onset of action was observed as early as 30 minutes following the initial dose of Dymista.

The subjective impact of seasonal allergic rhinitis on patient's health-related quality of life was evaluated by the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) (28 items in 7 domains (activities, sleep, non-nose/eye symptoms, practical problems, nasal symptoms, eye symptoms, and emotional) evaluated on a 7-point scale where 0=no impairment and 6=maximum impairment), which was administered to patients 18 years of age and older. An overall RQLQ score is calculated from the mean of all items in the instrument. A change from baseline of at least 0.5 points is considered a clinically meaningful improvement. In each of these trials, Dymista demonstrated a statistically significant greater decrease from baseline in the overall RQLQ than placebo, which ranged from -0.55 (95% CI -0.72, -0.39) to -0.80 (95% CI -1.05, -0.55). In these trials, the treatment differences between Dymista and the monotherapies were less than the minimum important difference of 0.5 points.

Pediatric Patients 6-11 Years of Age

The efficacy and safety of Dymista was evaluated in one randomized, multi-center, double-blind, placebo-controlled trial in 304 children 6 to 11 years of age with seasonal allergic rhinitis. Patients were randomized 1:1 to receive either one spray per nostril twice daily of Dymista or placebo (vehicle control) for 14 days. The design of the trial was similar to that of the adult trials.

The primary efficacy endpoint was the mean change from baseline in combined AM+PM reflective total nasal symptom score (rTNSS) over 2 weeks. Dymista was not statistically significantly different than placebo, but the results were numerically supportive (Table 5).

Table 5: Mean Change from Baseline in Reflective Total Nasal Symptom Scores over 2 weeks in Children age 6 to 11 years

How Supplied/Storage and Handling

Dymista nasal spray (NDC 0037-0245-23) is supplied as an amber glass bottle fitted with a metered-dose spray pump unit. The spray pump unit consists of a nasal spray pump with a white nasal adapter and clear plastic dust cap. Each bottle contains a net fill weight of 23 g and will deliver 120 metered sprays after priming [see Dosage and Administration (2.2)]. After priming [see Dosage and Administration (2.2)], each spray delivers a suspension volume of 0.137 mL as a fine mist, containing 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate (137 mcg/50 mcg). The correct amount of medication in each spray cannot be assured before the initial priming and after 120 sprays have been used, even though the bottle is not completely empty. The bottle should be discarded after 120 medicated sprays have been used.

Dymista should not be used after the expiration date “EXP” printed on the bottle label and carton.

Storage

Store upright with the dust cap in place at controlled room temperature 20° - 25°C (68° - 77°F). [See USP Controlled Temperature] Protect from light. Do not store in the freezer or refrigerator.

Patient Counseling Information

Somnolence has been reported in some patients (8 of 1,269 patients) taking Dymista in controlled clinical trials. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of Dymista [see Warnings and Precautions (5.1)].

Concurrent Use of Alcohol and other Central Nervous System Depressants

Advise patients to avoid concurrent use of Dymista with alcohol or other central nervous system depressants because additional reductions in alertness and additional impairment of central nervous system performance may occur [see Warnings and Precautions (5.1)].

Inform patients that glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Advise patients to inform his/her health care provider if a change in vision is noted while using Dymista [see Warnings and Precautions (5.3)].

Immunosuppression

Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Inform patients of potential worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.4)].

Effect on Growth

Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving Dymista [see Use in Specific Populations (8.4)].

Priming

Instruct patients to shake the bottle gently before each use and prime the pump before initial use and when Dymista has not been used for 14 or more days [see Dosage and Administration (2.2)].

Keep Spray Out of Eyes

Instruct patients to avoid spraying Dymista into their eyes.

Keep Out of Children's Reach

Instruct patients to keep Dymista out of the reach of children. If a child accidentally ingests Dymista, seek medical help or call a poison control center immediately.

Potential Drug Interactions

Advise patients that coadministration of Dymista and ritonavir is not recommended and to be cautious if Dymista is coadministered with ketoconazole [see Drug Interactions (7.2)].

U.S. Patents 8,163,723; 8,168,620

Manufactured by:
Cipla Ltd. Goa, India

Distributed by:
MEDA PHARMACEUTICALS®
Somerset, New Jersey 08873-4120

MEDA PHARMACEUTICALS and Dymista are registered trademarks of Meda
Pharmaceuticals Inc. or a related entity.

Made in India.

PATIENT INFORMATION

Dymista (Dy-Mist-A)

(azelastine hydrochloride and fluticasone propionate)
nasal spray

Important: For use in your nose only

What is Dymista?

Dymista is a prescription medicine used to treat symptoms of seasonal allergic rhinitis in people 6 years of age and older, who need treatment with both azelastine hydrochloride and fluticasone propionate.

Dymista may help to reduce your nasal symptoms including stuffy nose, runny nose, itching, and sneezing.

It is not known if Dymista is safe or effective in children under 4 years of age.

What should I tell my healthcare provider before using Dymista?

Before using Dymista tell your healthcare provider if you:

have had recent nasal sores, nasal surgery, or nasal injury

have eye or vision problems, such as cataracts or glaucoma (increased pressure in your eye)

have tuberculosis or any untreated fungal, bacterial, viral infections or eye infections caused by herpes

have been near someone who has chickenpox or measles

are not feeling well or have any other symptoms that you do not understand

have any other medical conditions

are pregnant or plan to become pregnant. It is not known if Dymista will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.

are breastfeeding or plan to breastfeed. It is not known if Dymista passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while using Dymista.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Dymista and other medicines may affect each other,causing side effects.

Especially tell your healthcare provider if you take:

ritanovir (Norvir) or medicines that contain ritanovir (commonly used to treat HIV infection or AIDS)

ketoconazole, fluconazole, or itraconazole (for fungal infections)

Ask your healthcare provider or pharmacist for a list of these medications, if you are not sure.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I use Dymista?

Read the Instructions for Use at the end of this leaflet for information about the right way to use Dymista.

An adult should help a young child use Dymista.

Dymista is for use in your nose only. Do not spray it into your eyes or mouth. If you spray Dymista into your eyes, flush your eye(s) with large amounts of water for 10 minutes and then call your healthcare provider.

Use Dymista exactly as your healthcare provider tells you to use it. Your healthcare provider will tell you how much Dymista to use and when to use it.

If a child accidentally swallows Dymista or you use too much Dymista, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while using Dymista?

Dymista can cause sleepiness or drowsiness. Do not drive, operate machinery, or do anything that needs you to be alert until you know how Dymista affects you.

Do not drink alcohol or take any other medicines that may cause you to feel sleepy while using Dymista. It can increase your chances of having serious side effects.

What are the possible side effects of Dymista?

Dymista may cause serious side effects including:

Sleepiness or drowsiness.

Nasal Problems. Symptoms of nasal problems may include:

crusting in the nose

nosebleeds

runny nose

hole in the cartilage between your nose (nasal septal perforation). A whistling sound when you breathe may be a symptom of nasal septal perforation.

Slow wound healing. You should not use Dymista until your nose has healed if you have a sore in your nose, if you have had surgery on your nose, or if your nose has been injured.

Thrush (candida), a fungal infection in your nose and throat. Tell your healthcare provider if you have any redness or white colored patches in your nose or mouth.

Eye problems, such as glaucoma or cataracts. Some people may have eye problems, including glaucoma and cataracts. You should have regular eye exams when using Dymista.

Immune system problems that may increase your risk of infections. Dymista may cause problems with the way your immune system protects your body against infection and increase your risk of infection. Avoid contact with people who have contagious diseases such as chickenpox or measles while you use Dymista. Symptoms of infection may include:

fever

aches or pains

chills

feeling tired

Adrenal Insufficiency. Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal insufficiency may include:

tiredness

weakness

nausea

vomiting

low blood pressure

Slowed or delayed growth in children. A child's growth should be checked regularly while using Dymista.

Call your healthcare provider or get medical help right away if you have symptoms of any of the serious side effects listed above.

The most common side effects of Dymista Nasal Spray include:

changes in taste

nosebleeds

headache

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of Dymista. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Throw away your Dymista bottle after using 120 sprays after initial priming. Even though the bottle may not be completely empty, you may not get the correct dose of medicine if you continue to use it.

Keep Dymista and all medicines out of reach of children.

General information about the safe and effective use of Dymista

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Dymista for a condition for which it was not prescribed. Do not give Dymista to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Dymista. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Dymista that is written for health professionals.

For more information, go to www.Dymista.com or call Meda Pharmaceuticals Inc. at 1-888-939-6478.

What are the ingredients in Dymista?
Active ingredients: azelastine hydrochloride and fluticasone propionate

Read the Instructions for Use before you start to use Dymista and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment. Before you use Dymista, make sure your healthcare provider shows you the right way to use it.

Shake the bottle gently before each use.

Your Dymista pump. (See Figure A)

Figure A

Instructions for Using Your Dymista Pump.

Before you use Dymista for the first time, you will need to shake the bottle gently and prime the pump.

For use in young children: An adult should help a young child use Dymista. (See Steps 1 through 12).

Priming your Dymista pump
Before you prime the bottle, shake it gently.

Hold the bottle upright with two fingers on the shoulders of the spray pump unit and put your thumb on the bottom of the bottle. Press upward with your thumb and release for the pumping action.

Repeat the pumping action until you see a fine mist. You should see a fine mist of the medicine after 6 pumps or less. (See Figure C)

To get a fine mist of medicine, you must repeat the pumping action fast and use firm pressure against the bottom of the bottle.

If you see a stream of liquid, the spray will not work right and may cause nasal discomfort.

If you do not use Dymista for 14 or more days, you will need to shake the bottle gently, and prime the pump with 1 spray or until you see a fine mist. If you do not see a fine mist, clean the tip of the spray nozzle. See the cleaning section below.

Once you see the fine mist of medicine, your Dymista pump is ready for use.

Figure C

Using your Dymista:

For use in young children: An adult should help a young child use Dymista.

Step 3.

Gently blow your nose to clear nostrils. (See Figure D)

Figure D

Step 4.

Shake the bottle gently. Close 1 nostril with a finger. Tilt your head forward slightly. Keep the bottle upright and carefully place the spray pump tip ¼ to ½ inch into your other nostril. (See Figure E)

Figure E

Step 5.

For each spray firmly press the pump 1 time. Keep your head tilted down and at the same time, gently breathe in through your nostril. (See Figure F) Do not spray directly onto the nasal septum (the wall between your 2 nostrils).

Repeat Step 5 in your other nostril.

Do not tilt your head back. This will help to keep the medicine from going into your throat.

If the medicine goes into your throat you may get a bitter taste in your mouth. This is normal.

Figure F

Step 6.

When you finish using Dymista, wipe the spray tip with a clean tissue or cloth. Put the dust cap back on the spray pump tip of the bottle. (See Figure G)

Figure G

Each bottle of Dymista contains enough medicine for you to spray medicine from the bottle 120 times. After initial priming, do not use your bottle of Dymista after 120 sprays. You may not receive the right amount of medicine. Keep track of the number of sprays you use from your bottle of Dymista and throw away the bottle even if it has medicine left in it.

Do not count any sprays used for initially priming the bottle.

To Clean the Spray Pump Tip:

Your Dymista should be cleaned at least 1 time each week. To do this:

Step 7.

Remove the dust cap and then gently pull upward on the spray pump unit to remove it from the bottle. (See Figure H)

Allow to dry completely. When dry, place the spray pump unit and dust cap back on the bottle. (See Figure J)

Figure J

Step 10.

If the spray pump unit becomes blocked, it can be removed as instructed above in Step 7 and placed in warm water to soak.

Do not try to unblock the spray pump unit by inserting a pin or other sharp object. This will damage the spray pump unit and cause you not to get the right dose of medicine.

Step 11.
After the spray pump unit is unblocked, rinse the applicator and cap with cold water, and allow them to dry as in Step 10 above. When dry, place the spray pump unit back on the bottle and put the dust cap on the spray pump tip.

Step 12.
Reprime the bottle as in Steps 1 and 2 above. Replace the dust cap and your Dymista is ready for use.

This Patient Package Insert and Instructions for Use has been approved by the U.S. Food and Drug Administration.